A protocol of a systematic review on deep brain stimulation surgery and its efficacy in addressing substance abuse addiction

Abstract Background Pharmacotherapy and psychotherapeutic approaches are still the mainstay first line of treatment for substance use disorder. However, the path to rehabilitation and cessation of dependence often proves uncertain and laborious, with risks of relapse being considerable despite exposure to current therapeutic modalities. For cases of treatment‐refractory addiction, deep brain stimulation (DBS) interventions can prove a more effective long term therapeutic solution for the patient. Objectives The aim of the study will be to systematically assess whether attempts at correcting substance use disorder via DBS neurosurgical interventions have been successful in inducing remission or ameliorating relapse rates. Methods The current study will analyze available literature from database inception up to 15th April 2023, reviewing all publications documenting results achieved with human patients undergoing DBS for substance use disorder in PubMed, Ovid, Cochrane, and Web of Science. The electronic database search will exclude animal studies in the field and focus solely on the application of DBS for the purposes of addressing addiction disorders. Results The expectation is for a reduced number of trial results to have been reported, namely due to the relatively recent application of DBS to address severe addiction. Nonetheless, numbers should be in sufficient amount to inform about the efficacy of the intervention. Conclusion This study will attempt to demonstrate the viability of DBS as a solution for tackling treatment‐refractory substance use disorder, proposing it as a valid therapeutic option that can deliver robust results and help combat an expanding societal plague that is drug dependence.


| INTRODUCTION
The potential of deep brain stimulation (DBS) surgery was first explored in the late 1980s in patients presenting with movement disorder symptomatology, for such conditions as Parkinson's Disease, dystonia and essential tremor. 1 It was later incorporated in the treatment of neuropsychiatric pathologies, including Tourette's Syndrome, obsessive compulsive disorder, mood and eating disorders. 2 Nonetheless, the therapeutic possibilities of electrical stimulation of the brain had been explored at least since the 1930s in ablation interventions intended to provide resolution for seizures in epilepsy. 3 There have been rapid advances in the past decade within this branch of functional neurosurgery, to the extent that it is now possible to implant electrodes in targeted areas in the brain, such as the nucleus accumbens and the subthalamic nucleus. 4 The intent is to modulate neural pathways in the mesolimbic and mesocortical dopaminergic system rather than ablating them, thus controlling the dependence on substances of abuse which debilitate the lives of many patients and their significant others, when cases are severe and multiple non-DBS attempts have failed. 5 Addiction entails a chronically relapsing disorder with presentation of compulsions for seeking and consuming substances of abuse, that despite triggering repercussions still persist in time. 6 Craving the substance is due to neural circuitry changes that result in a marked difficulty to suppress the urge to seek the substance at the basis of the dependence. 7 Risk of relapse in substance abuse patients is currently high when addressed with conventional pharmacotherapeutic methods. For alcoholics the rates reach around 70% within the first year of therapy and for opioid addicts it can reach up to 91%. 8 Socioeconomic costs are significant and they increase exponentially over time as interrelated complications present a cumulatively detrimental effect. The risk of the individual being alienated from social support structures and potential financial ruin is higher as the patient gets entangled in physiological reward circuitry processes over which control only grows more ephemeral. 9 This protocol is intended to lay groundwork and prospects for a systematic review that will observe the efficacy of DBS neurosurgical interventions in substance use disorders.

| RESEARCH HYPOTHESIS
Do DBS neurosurgical interventions contribute to effectively reduce or even extinguish relapse episodes in substance use disorder patients presenting treatment-refractory addiction pathology?

| Conceptual framework
The relevance of this project is the need for an updated compilation of reported patient cases to have better insight into the authenticated efficacy of the intervention and hence the possibility of more widespread DBS use in scenarios of severe addiction and frequent relapses to bolster traditional pharmaco-psychiatric modalities of treatment. The keywords that served as basis for the search protocol were "deep brain stimulation" and "addiction" as well as keywords referring to the various potential substances of abuse under investigation, which included the terms "heroin," "opioid," "smoking," "nicotine," "alcohol," "benzodiazepines," "methamphetamines," and "cocaine."

| Patients and methodology
For PubMed the following related MeSH terms were retrieved and employed alongside specific search words derived from the afore- and "Benzodiazepine-Related Disorders." For the Ovid Embase database search the following subject headings were used alongside relevant search terms: "brain depth stimulation/," "addiction/," "abuse/," "alcohol/," "smoking/," "nicotine/," "tobacco/," "opiate/," "diamorphine/," "benzodiazepine/," "methamphetamine/," and "cocaine/." The final study results of retrieved publications will be presented in appropriate tables, highlighting major characteristics and relevant outcomes of each study, for adequate compilation or details for review and satisfactory comparison. All participants in the studies will be required to have demonstrated problematic dependence on a substance for which they would be subjected to DBS for. This should be for a period of at least 1 year, with patients having been diagnosed as suffering from a dependence disorder. Having undertaken previous treatment attempts to address the addiction disorder will not be mandatory, as this will also depend on the specific substance. With regards to inclusion criteria the human subjects could be of any age, sex and ethnicity, and the substance referred to in the studies could be any that could lead to dependence. This while observing exclusion criteria mentioned above. The studies had to focus on addiction interventions with DBS being applied on human subjects to address substance abuse disorders.

| Risk of bias analysis
Two independent investigators will evaluate each study for risk of bias using the Cochrane Risk of Bias tool 2.0 (ROB 2) for randomized trials 35 38 The potential disruption to the lives of significant others and the economic impact on society when attempting to manage chronic cases of heavy dependence and drug abuse can be high. 39 The most frequently abused substance globally is alcohol, followed by opioids. 40 Illicit drug use, which comprises opioids, cocaine, cannabis and amphetamines, is directly or indirectly involved in the demise of around 600,000 persons every year. 41 It is estimated that around 2015, the potent synthetic opioid fentanyl and its analogues had made a significant impact in the illicit US drug market, with exponential growth year on year. 42 Detected also in cocaine, heroin and methamphetamine supplies since then, 43 it has contributed to a higher number of overdose deaths-a sixfold increase from 2015 to 2020, with 56,516 directly attributable to fentanyl alone in 2020 in the United States. 44 Worldwide, the burden of disease and injury attributable to the use of alcohol is 5.1%. Deaths resulting from alcohol misuse amount to 5.3% globally, with 13.5% of all deaths for younger individuals within the 20-39 age bracket being due to alcohol. 45 Nicotine is estimated to cause 7.7 million deaths yearly, with 20% of all male deaths worldwide being attributable to cigarette smoking. The number of smokers has increased to 1.1 billion people, and it is crucial to note that 9 in 10 of all smokers are considered to be addicted by 25 years of age. 41 The mesolimbic dopaminergic system in the brain is part of the reward pathway that when subjected to unregulated processes leads to the creation and maintenance of addictive behaviors. Via the release of dopamine into the nucleus accumbens the pleasure cycle is regulated over the wanting or desire phase and the consummatory "liking" phase, as well as the reinforcement process generating learnt cues associated with the reward stimulus. 46 Therapeutic management of some psychiatric and movement disorders have now incorporated DBS in their treatment plan due to the unrivaled DIMECH and RANJAN | 3 of 6 benefits this neurosurgical technique has offered to patients. 47 DBS interventions on the brain's reward system, targeting the nucleus accumbens primarily, hold promise for similarly successful results, presenting a therapeutic option for cases of severe addiction where conservative attempts have failed repeatedly. 48

| Novelty of the study
The research will contribute improved dissemination of knowledge related to this relatively young field offering new therapeutic possibilities for patients who fail to overcome relapse and plunge back into a vicious cycle of despair that can significantly dent the psychosocial and economic resources of the individual, with ensuing long term societal ramifications. F I G U R E 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram according to 2020 guidelines 10 showing phases of our study.

Redoy Ranjan is an Editorial Board member of Health Science
Reports and a co-author of this article. To minimize bias, he was excluded from all editorial decision-making related to the acceptance of this article for publication. The other author declares no conflict of interest.

DATA AVAILABILITY STATEMENT
This is an ongoing project and the data that support the findings of this study are available on request from the corresponding author.
The data are not publicly available due to privacy or ethical restrictions. Dr. David Zammit Dimech had full access to all of the data in this study and took complete responsibility for the integrity of the data and the accuracy of the data analysis.

TRANSPARENCY STATEMENT
The lead author Redoy Ranjan affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.